INTRODUCTION — Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses. Influenza occurs in outbreaks and epidemics worldwide, mainly during the winter season.
Issues related to pharmacology and resistance of antiviral drugs against influenza will be reviewed here. The approach to use antiviral agents for treatment and prevention of influenza, including the approach to treatment of suspected or known infection due to drug-resistant influenza virus, is discussed separately:
●(See "Seasonal influenza in nonpregnant adults: Treatment".)
●(See "Seasonal influenza and pregnancy".)
●(See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention".)
●(See "Seasonal influenza in children: Management".)
●(See "Seasonal influenza in children: Prevention with antiviral drugs".)
Updated information about influenza activity and antiviral resistance can be found on the United States Centers for Disease Control and Prevention website and the World Health Organization website.
DRUG CLASSES — Classes of antiviral drugs for treatment of influenza include (table 1) [1-3]:
●Neuraminidase inhibitors − Neuraminidase inhibitors include oseltamivir, zanamivir, peramivir, and laninamivir (approved for use in Japan but remains investigational elsewhere); they are active against influenza A and B. Neuraminidase inhibitors interfere with release of progeny influenza virus from infected cells, thereby preventing new rounds of infection.
●Endonuclease inhibitor − Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease mediated by the viral polymerase acidic protein; it is active against influenza A and B.
●Adamantanes − Adamantanes include amantadine and rimantadine; they are active against influenza A. These drugs target the M2 protein of influenza A, which forms a proton channel in the viral membrane that is essential for viral replication.
Due to emergence of high rates of adamantane resistance among influenza A viruses, the United States Centers for Disease Control and Prevention (CDC) recommends that adamantanes not be used for the treatment of influenza in the United States [1].
Neuraminidase inhibitors — Oseltamivir, zanamivir, peramivir, and, laninamivir (approved for use in Japan but remains investigational elsewhere) are structurally related drugs with activity against seasonal influenza as well as avian influenza A strains [4,5]. (See "Avian influenza: Epidemiology and transmission".)
General principles
Mechanism of action — Influenza hemagglutinin is a viral surface glycoprotein that binds to sialic acid residues on respiratory epithelial cell surface glycoproteins for initiation of infection. After viral replication, progeny virions are also bound to the host cell via sialic acid residues on cell surface glycoproteins. Neuraminidase-mediated removal of these sialic acid moieties permits release of progeny virions.
Neuraminidase inhibitors are sialic acid analogs that competitively inhibit neuraminidase; these drugs interfere with the release of progeny influenza virus from infected cells, thereby preventing new rounds of infection [6].
Pharmacokinetics
●Oseltamivir − Oseltamivir phosphate is administered orally. It is available as a capsule or powder for liquid suspension that is rapidly metabolized to the active form, oseltamivir carboxylate [7]. A single 100 mg dose yields a peak plasma concentration of 250 mcg/L, with an elimination half-life of approximately eight hours [8]. Food does not affect peak concentration or overall systemic exposure. Elimination is primarily renal, and dose reduction is recommended for patients with reduced creatinine clearance.
●Zanamivir − Zanamivir is administered as an inhaled powder and has poor oral bioavailability. Approximately 15 percent of inhaled zanamivir is deposited in the bronchi and lungs, with the remainder staying in the oropharynx [9]. It is highly concentrated in the respiratory tract [6]. Excretion is primarily renal, but, given limited systemic bioavailability, there is no need to modify the dose in patients with renal insufficiency. The pulmonary half-life is 2.8 hours [10]. Zanamivir inhalation powder should not be reconstituted in any liquid formulation and is not recommended for use in nebulizers or mechanical ventilators [11].
An intravenous (IV) formulation of zanamivir is available in the European Union and the United Kingdom but not in the United States. The usual recommended dose in adults is 600 mg every 12 hours for 5 to 10 days. The drug is renally cleared with a half-life of approximately two to three hours in healthy individuals. Dose adjustment is necessary in the setting of renal insufficiency [12].
●Peramivir − Peramivir is administered as a single IV dose because it has a strong and prolonged affinity for influenza virus neuraminidase [13-15]. The recommended dose of peramivir is 600 mg IV and the elimination half-life in healthy adults is approximately 20 hours. Elimination is primarily renal, so dosing must be adjusted in the setting of renal insufficiency.
Adverse effects — Issues related to adverse effects are discussed separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral efficacy and adverse effects'.)
Drug resistance — Updated information about resistance patterns among circulating influenza viruses can be found at the CDC website. A comprehensive list of neuraminidase inhibitor resistance mutations can be found at the World Health Organization (WHO) website.
Most neuraminidase inhibitor resistance affects oseltamivir and peramivir but not zanamivir. Resistance to the neuraminidase inhibitors appears to arise less readily than adamantane resistance.
Oseltamivir
Epidemiology
●General principles – In general, oseltamivir resistance (and peramivir cross-resistance) is rare; since 2009, 99 percent of influenza virus isolates tested in the United States have been susceptible to neuraminidase inhibitors [1,16].
Prior to 2007, oseltamivir resistance was rare in clinical settings; in clinical trials, it emerged in 1 to 5 percent of cases [17-19].
During the 2007-2008 influenza season, oseltamivir-resistant isolates emerged in Europe [19-22]. None of the patients in the initial reports of oseltamivir-resistant influenza had been taking oseltamivir, suggesting transmission of resistant virus between individuals [20,23]. The severity of illness due to oseltamivir-resistant influenza was similar to oseltamivir-susceptible influenza [24,25].
During the 2008-2009 influenza season, high rates of oseltamivir resistance (>90 percent) were observed in the United States, Australia, and the Philippines [26,27].
During the 2009 H1N1 influenza A pandemic, the predominantly oseltamivir-susceptible pandemic strain replaced the oseltamivir-resistant seasonal H1N1 strain worldwide [28]. A small minority of pandemic H1N1 influenza A virus isolates with oseltamivir resistance were detected from patients in several countries, including Japan, the United States, China, Hong Kong, Singapore, Vietnam, Denmark, and Australia [29-38]. Among 37 cases in the United States, 76 percent occurred among immunocompromised patients and 89 percent occurred among patients who had received oseltamivir; thus, these appear to be actual risk factors for oseltamivir resistance [35].
However, in one community cluster of oseltamivir-resistant pandemic H1N1 influenza A infection in Vietnam, none of the individuals had received oseltamivir prophylaxis [33]. In addition, sustained community transmission of oseltamivir-resistant pandemic H1N1 influenza A was identified in 29 individuals in New South Wales, Australia [37,38]. Hemagglutinin and neuraminidase sequence analysis indicated that the resistant strains were closely related, suggesting spread of a single variant. Only one patient had received oseltamivir prior to collection of a respiratory specimen for resistance testing.
The neuraminidase mutation H275Y, which caused oseltamivir resistance among seasonal H1N1 influenza A isolates beginning in 2007, was also detected in isolates from patients with oseltamivir-resistant pandemic H1N1 influenza A infection [32,39]. Furthermore, community clusters of oseltamivir resistance in untreated individuals may be explained by the presence of permissive neuraminidase mutations that restore the viral fitness of H275Y [38,40].
●Risk factors – Factors associated with the emergence of antiviral drug resistance include the administration of postexposure prophylaxis with a neuraminidase inhibitor (particularly if underdosed), immunosuppression, and prolonged antiviral treatment [41,42].
The increased risk among immunocompromised patients may be attributable to prolonged viral shedding despite antiviral therapy [43-49]. In one report of three immunocompromised patients, resistant influenza variants developed during treatment [46]. One patient received oseltamivir prophylaxis when a close contact was diagnosed with influenza; she subsequently developed respiratory symptoms and was started on full treatment doses of oseltamivir. Despite this, she died of influenza B infection; a virus subpopulation was recovered with neuraminidase and hemagglutinin mutations conferring reduced susceptibility to oseltamivir and zanamivir. Two other patients developed resistant influenza A virus with mutations in genes encoding the M2, neuraminidase, and hemagglutinin proteins; both viruses were resistant to oseltamivir but susceptible to zanamivir.
A similar pattern of oseltamivir resistance among immunocompromised patients was observed during the 2009 H1N1 influenza A pandemic. Two nosocomial clusters of oseltamivir-resistant pandemic H1N1 influenza A infection were identified in Wales and the United States [50,51]. In one study, 8 of 10 patients had oseltamivir-resistant virus and 4 of 8 were infected by direct transmission of resistant virus [50].
Mechanisms
●Influenza A − Mechanisms of resistance observed among influenza A viruses include [52,53]:
•Neuraminidase mutations − Mutations resulting in amino acid substitutions in the neuraminidase conserved active site (either part of catalytic residues or so-called framework amino acids surrounding the active site) usually result in drug-specific resistance.
-H275Y mutation − The most common neuraminidase mutation occurring in H1N1 viruses is the H275Y mutation (histidine to tyrosine substitution at amino acid 275); it is the mutation responsible for the oseltamivir resistance that emerged and spread among seasonal H1N1 influenza A viruses between 2007 and 2009 (but rarely among 2009 pandemic and postpandemic seasonal H1N1 influenza A viruses) [19,54].
The H275Y mutation reduces susceptibility of H1N1 influenza virus to oseltamivir (by more than 400-fold) and also reduces susceptibility to peramivir [55] but does not cause resistance to zanamivir in vitro [23,56-58]. This mutation is considered by WHO as clinically relevant due to its frequency and the availability of clinical data showing reduced treatment efficacy [59].
A nosocomial cluster of infection with an H1N1 influenza A virus harboring the H275Y mutation suggested that the mutated virus was transmissible and retained pathogenicity [60], possibly due to the presence of permissive or compensatory mutations, increasing the cell surface expression of the neuraminidase [61].
The H1N1 virus responsible for the 2009 pandemic, which has continued to circulate, has generally retained oseltamivir susceptibility, with approximately 1 percent of viruses exhibiting resistance, most frequently in immunocompromised patients [42].
The epidemiology of influenza viruses possessing the H275Y mutation is presented above. (See 'Epidemiology' above.)
-Other mutations – Less frequent mutations among H1N1 viruses include alterations at residues I223 and S247N (table 2) [62]. These are associated with low levels of oseltamivir resistance (usually less than a 10-fold increase in 50 percent inhibitory concentration [IC50] values) but can potentiate resistance conferred by the H275Y mutation.
Among H3N2 viruses, the most frequent mutations conferring oseltamivir resistance are E119V and R292K; R292K is also associated with reduced zanamivir inhibition [63]. Mutants with deletion of a few amino acids in the neuraminidase that exhibit resistance to oseltamivir have been observed in patients [43,44].
•Hemagglutinin mutations − Mutations in the hemagglutinin at or near the site that binds to sialic acid residues, reducing the efficiency of viral binding; this leads to diminished dependence on neuraminidase for viral replication. Such mutations confer broad cross-resistance in vitro to oseltamivir, zanamivir, and some investigational neuraminidase inhibitors; however, these mutations are of uncertain clinical significance.
●Influenza B − Oseltamivir resistance has been observed rarely among influenza B viruses; neuraminidase mutations conferring oseltamivir resistance are summarized in the table (table 2) [46,62,64-70].
During the 2010-2011 influenza season, a novel neuraminidase substitution, I221V, associated with reduced susceptibility to oseltamivir (two- to sixfold increase in IC50) was detected in North Carolina [67]. Among 209 clinical isolates of influenza B, the I221V mutation was detected in 22 percent of cases in North Carolina; it was observed in 10 percent of cases in South Carolina and 0.3 percent of cases from 45 other states. This mutation was not detected during the subsequent season.
Zanamivir — Very little zanamivir resistance has been observed, and the majority of cases of oseltamivir resistance have not resulted in cross-resistance to zanamivir. Few studies have directly compared the prevalence of oseltamivir and zanamivir resistance, given the rarity of zanamivir resistance and the less frequent use of zanamivir.
A few cases of zanamivir resistance associated with changes at residue 119 have been described among immunocompromised individuals (table 2). The E119I H3N2 variant, detected in a 2-year-old boy with lymphoproliferative disorder, exhibited reduced susceptibility to both zanamivir and peramivir and highly reduced susceptibility to oseltamivir [71].
Other substitutions were identified in patients infected with the 2009 H1N1 influenza A pandemic virus. In one report, a stem cell transplant recipient developed H1N1 influenza with both H275Y and E119D neuraminidase mutations; he had received both oseltamivir and zanamivir [72]. The H275Y mutation conferred resistance to oseltamivir and peramivir, whereas the E119D mutation conferred resistance to multiple neuraminidase inhibitors (zanamivir, oseltamivir, peramivir, and laninamivir). The combination of the two mutations increased the magnitude of neuraminidase inhibitor resistance further.
Another report describes an immunocompromised infant who developed influenza infection caused by an H1N1 influenza strain possessing H275Y and E119G (with glycine replacing glutamic acid at position 119) neuraminidase mutations following prolonged treatment with oseltamivir and zanamivir [73]. These mutations conferred resistance to multiple neuraminidase inhibitors.
Peramivir — For H1N1 viruses, there is generally cross-resistance between oseltamivir and peramivir; the H275Y mutation in the neuraminidase of H1N1 viruses confers high levels of resistance to both drugs [32].
Multidrug resistance
●Multineuraminidase resistance − The E119D/G mutations have been associated with resistance to multiple neuraminidase inhibitors in pandemic H1N1 isolates [72,73]. In addition, changes at residue 223 (I223 R/V) in the 2009 H1N1 influenza A pandemic virus confer various levels of resistance to many neuraminidase inhibitors [74,75], especially when combined with the H275Y mutation [62].
●Dual oseltamivir-adamantane resistance – Dual resistance to oseltamivir and adamantanes correlates with the extent of oseltamivir resistance. Among 1457 seasonal H1N1 influenza A isolates collected worldwide between 2008 and 2010, 28 viruses (1.9 percent) with dual resistance were detected from five countries [76]. Twenty-one of the dually resistant viruses were collected from China, four from the United States, and one each from Canada, Kenya, and Vietnam. The resistant viruses belonged to four genetic backgrounds and resulted from several mechanisms, including exchange of M and neuraminidase genes between clade 2B and clade 2C variants, emergence of mutations conferring adamantane resistance in oseltamivir-resistant viruses during antiviral therapy, transmission from others, and possibly spontaneously [76,77].
Baloxavir
General principles — Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease; it blocks influenza proliferation by inhibiting the initiation of mRNA synthesis [78]. Baloxavir has activity against influenza A viruses, including H7N9 and H5N1 viruses, and influenza B viruses [78]. It has activity against influenza viruses that are resistant to oseltamivir and it appears to have synergistic activity with neuraminidase inhibitors.
Following administration, baloxavir marboxil undergoes hydrolysis to its active form, baloxavir, which is metabolized by UGT1A3 and CYP3A [78]. Baloxavir is primarily eliminated by biliary excretion. Its mean elimination half-life is 96 hours.
Coadministration of baloxavir with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (eg, calcium, iron, magnesium, selenium, zinc) should be avoided.
In a phase III trial, adverse events that were considered to be related to baloxavir were uncommon (eg, diarrhea in 1.8 percent) [79]. Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema, erythema multiforme) have been reported in postmarketing surveillance [80].
Drug resistance — Emergence of polymerase acidic (PA) protein variants with I38T/M/F or E23K substitutions, which confer reduced susceptibility to baloxavir, has been described with variable frequency following a single dose of baloxavir (in up to 10 percent in trials of adolescents and adults [79,81] and in up to 24 percent in children [82-84]). In one study, these variants were associated with transient rises in viral titers, prolonged viral detection, and slower initial improvement of symptoms [81]. The emergence of resistance after a single dose raises concerns about the long-term utility of this drug as monotherapy, particularly if it is used widely.
The I38T substitution resulted in severely impaired replication in one in vitro study [85]; however, subsequent animal studies have suggested that viruses with the I38T substitution have similar replicative fitness, pathogenicity, and transmissibility as wild-type viruses [86-88]. Human transmission of this resistant variant has been documented [89,90]. The I38T substitution is considered by WHO as clinically relevant due to its frequency of occurrence and the availability of clinical data suggesting reduced treatment efficacy [91]. Other less frequent baloxavir resistance substitutions, such as I38F/M and E23K/G in the PA protein, have been reported [86,92]. For a comprehensive list of baloxavir resistance mutations, please refer to the WHO website.
Adamantanes — Amantadine and rimantadine are closely related adamantanes (also called M2 inhibitors) with comparable efficacy. Widespread emergence of adamantane-resistant influenza A strains has limited the clinical utility of these drugs; they should not be used routinely for influenza treatment or prophylaxis.
Mechanism of action — Resistance to amantadine and rimantadine is mediated by single nucleotide changes involving the transmembrane portion of the M2 molecule [93,94]. Such mutations confer cross-resistance between the adamantanes [94].
Drug resistance
●General principles − The adamantanes target the M2 protein of influenza A viruses only. This protein forms an ion channel in the viral membrane that is essential for efficient viral replication [95-97].
Resistance to amantadine and rimantadine is mediated by single amino acid change (usually S31N) that has no effect on virus replication [77,98]. Such mutations confer cross-resistance between the adamantanes [94]. The rate of spontaneous mutations resulting in drug resistance in tissue culture is quite high, between 1:1000 and 1:10,000 [94]. Adamantane resistance can occur spontaneously or emerge as soon as two to three days following initiation of adamantane treatment [94]. Resistant viruses are genetically stable, virulent, and transmissible [99,100].
●Mechanisms − Single-point mutations in the codons for amino acids at positions 26, 27, 30, 31, or 34 of the M2 protein affect the transmembrane portion of this protein, the M2 ion channel, and confer cross-resistance to both amantadine and rimantadine [93,94,101]. The mutation at position 31 is most common.
●Epidemiology − Widespread dissemination of adamantane-resistant influenza was first noted in 2003 to 2004 among H3N2 viruses, primarily in Asia [101]. Substantial rates of adamantane resistance are now present worldwide in both H3N2 and H1N1 strains.
In the United States, the incidence of resistance was less than 2 percent until the 2004-2005 influenza season, when 15 percent of isolates demonstrated resistance [101,102]. During the 2005-2006 season, 92 percent of H3N2 influenza A viruses isolated from patients in 26 states contained an amino acid substitution at position 31 of the M2 protein, which confers resistance to both amantadine and rimantadine [103,104]. During the 2009-2010 influenza season in the United States, all H3N2 influenza A and 2009 pandemic H1N1 isolates tested were resistant to the adamantanes [105].
CLINICAL APPROACH TO DRUG RESISTANCE — Issues related to management of patients with suspected or known infection due to drug-resistant influenza virus are discussed separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral resistance'.)
SUMMARY
●Drug classes − Classes of antiviral drugs for treatment of influenza include neuraminidase inhibitors (oseltamivir, zanamivir, peramivir, and laninamivir), endonuclease inhibitor (baloxavir), and adamantanes (amantadine and rimantadine) (table 1). (See 'Drug classes' above.)
●Clinical approach to drug resistance − Issues related to management of patients with suspected or known infection due to drug-resistant influenza virus are discussed separately. (See "Seasonal influenza in nonpregnant adults: Treatment", section on 'Antiviral resistance'.)
●Neuraminidase inhibitor resistance
•Epidemiology – Antiviral resistance is rare (approximately 1 percent); risk factors include administration of postexposure prophylaxis, prolonged antiviral treatment, and immunosuppression. (See 'Epidemiology' above.)
•Mechanisms − Mechanisms of neuraminidase inhibitor resistance include mutations in neuraminidase (most commonly H275Y) and hemagglutinin (table 2). (See 'Mechanisms' above.)
●Baloxavir resistance − The emergence of resistance after a single dose of baloxavir raises concerns about the long-term utility of this drug as monotherapy. The most common resistance mutation is I38T in the polymerase acidic protein. (See 'Baloxavir' above.).
●Adamantane resistance − Widespread emergence of adamantane-resistant influenza A strains has limited the clinical utility of these drugs; they should not be used routinely for influenza treatment or prophylaxis. (See 'Adamantanes' above.)
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